Imaging of Angiogenesis Angiogenesis is an important process in the growth and spread of cancer. It is a topic of great interest to scientists and clinicians in the CCR who are utilizing anti-angiogenic strategies for treatment and therefore, it is of importance that the MIP address angiogenesis in its program of targeted tumor imaging. Here, we describe the pre-clinical and clinical aspects of angiogenesis imaging in MIP. Pre-Clinical Research There are two approaches to angiogenesis imaging: physiologic or functional studies that investigate the flow and permeability dynamics of vessels within tumors and a molecular targeted approach. We have investigated both aspects. The MIP has developed expertise in the performance of dynamic contrast enhanced MRI (DCE-MRI)with low molecular weight and macromolecular contrast agents(1-3). This is a seemingly straightforward test in which a bolus of a paramagnetic contrast agent is followed by the rapid acquisition of images. The images are then analyzed and curve fitting parameters are derived that reflect the physiology of the vasculature. Interestingly, while popular, there has been little validation of this method compared to other well known methods of measuring vessel permeability. We have conducted ultrastructure studies in conjunction with Donald McDonald's lab in UCSF(4). We conducted an murine study in which radiolabeled (14C) permeability agent was compared (using Quantitative AutoRadiography (QAR) with DCE-MRI in a brain tumor model(5). We found excellent correlation between the QAR results and the parameter Ktrans which is derived from DCE-MRI. We have also performed validation studies in treatment models involving TNFalpha in conjunction with Steve Libutti's laboratory of Angiogenesis)(6). Over the past year we have developed targeted integrin imaging (optical and radionuclide) using cyclized RGD. This work could result in a targeted imaging agent for directly visualizing angiogenic vessels. However, work in this area has been disappointing probably owing to inadequate models. New targeted imaging agents are being sought to further pursue this work. Clinical studies The MIP provides a DCE-MRI "service" to investigators in the Clinical Center. This is now considered a routine study at NIH due to our efforts. One of the clinical fellows in MIP, identifies a target lesion and ensures that the proper study is performed each time the patient returns. The fellow also provides results to the investigators for research purposes. The MIP is providing this service to 5 active protocols by CCR investigators who are looking at various anti-angiogenic agents. Such work, by its nature, is difficult and publications have been slow to accrue, however in the past year two publications have appeared from a breast cancer trial conducted by Dr. Swain before she left NCI(7, 8). These demonstrate profound changes in vessel permeability in responders to Bevacizumab followed by high dose intensive chemotherapy. The role of DCE-MRI was compared to other biomarkers that were studied and it was found to be among the more useful of the predictive markers. The MIP is also about to conduct a study with Dr. Howard Fine using a PET agent that targets the AvB3 and AvB5 integrins. This 18F labeled PET agent is made by GE Healthcare and is being offered to NCI for trial purposes. Because we have been able to develop a clinical team (2 nuclear medicine physicians (Karen Kurdziel, Greg Ravizzini), one body radiologist (Peter Choyke), one neuroradiologist (Dima Hammoud) as well as support staff in the form of Nurse Practitioners and Research Nurses, we are prepared to take advantage of this opportunity that would formerly not have been possible. We are currently working with GE and Dr. Fine (Neurooncology Branch) and Dr. Gianconne (Medical Oncology Branch) to develop suitable imaging trials in glioblastoma and lung cancer respectively to test this novel angiogenesis agent. 1. Barrett, T., Brechbiel, M., Bernardo, M., and Choyke, P. L. MRI of tumor angiogenesis. J Magn Reson Imaging, 26: 235-249, 2007. 2. Barrett, T., Kobayashi, H., Brechbiel, M., and Choyke, P. L. Macromolecular MRI contrast agents for imaging tumor angiogenesis. Eur J Radiol, 60: 353-366, 2006. 3. Xu, H., Regino, C. A., Bernardo, M., Koyama, Y., Kobayashi, H., Choyke, P. L., and Brechbiel, M. W. Toward improved syntheses of dendrimer-based magnetic resonance imaging contrast agents: new bifunctional diethylenetriaminepentaacetic acid ligands and nonaqueous conjugation chemistry. J Med Chem, 50: 3185-3193, 2007. 4. Ocak, I., Baluk, P., Barrett, T., McDonald, D. M., and Choyke, P. The biologic basis of in vivo angiogenesis imaging. Front Biosci, 12: 3601-3616, 2007. 5. Ferrier, M. C., Sarin, H., Fung, S. H., Schatlo, B., Pluta, R. M., Gupta, S. N., Choyke, P. L., Oldfield, E. H., Thomasson, D., and Butman, J. A. Validation of dynamic contrast-enhanced magnetic resonance imaging-derived vascular permeability measurements using quantitative autoradiography in the RG2 rat brain tumor model. Neoplasia, 9: 546-555, 2007. 6. Tang, J. S., Choy, G., Bernardo, M., Thomasson, D., Libutti, S. K., and Choyke, P. L. Dynamic contrast-enhanced magnetic resonance imaging in the assessment of early response to tumor necrosis factor alpha in a colon carcinoma model. Invest Radiol, 41: 691-696, 2006. 7. Wedam, S. B., Low, J. A., Yang, S. X., Chow, C. K., Choyke, P., Danforth, D., Hewitt, S. M., Berman, A., Steinberg, S. M., Liewehr, D. J., Plehn, J., Doshi, A., Thomasson, D., McCarthy, N., Koeppen, H., Sherman, M., Zujewski, J., Camphausen, K., Chen, H., and Swain, S. M. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol, 24: 769-777, 2006. 8. Thukral, A., Thomasson, D. M., Chow, C. K., Eulate, R., Wedam, S. B., Gupta, S. N., Wise, B. J., Steinberg, S. M., Liewehr, D. J., Choyke, P. L., and Swain, S. M. Inflammatory Breast Cancer: Dynamic Contrast-enhanced MR in Patients Receiving Bevacizumab Initial Experience. Radiology, 244: 727-735, 2007.